Abstract

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter–driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.

Figure 1

(A) Relative contribution of 24-hour Na+ (2UNaV), K+ (2UKV), and urea (UUreaV) excretion to total 24-hour Na+, K+, and urea osmolyte excretion in mice on a LS diet (n = 6) or a HS diet with isotonic saline to drink (HS+saline; n = 8), and in 10 men consuming a 6-g/d or 12-g/d salt diet. Two-fold values of UNaV and UKV are given to account for their unmeasured accompanying anions. (B) Relationship among surplus 2Na+, 2K+, and urea osmolyte excretion (U2Na2KUreaV) and surplus water excretion in mice on a 0.1% NaCl diet with tap water (LS) (n = 6) or a 4% NaCl diet with 0.9% saline (HS+saline) (n = 8) for 2 consecutive weeks. (C) Relationship between surplus U2Na2KUreaV and surplus water excretion in all mice and human subjects presented in Table 1. (D) Relationship between surplus U2Na2KUreaV and FWC in the same mice and human subjects. (E) Relationship between surplus U2Na2KUreaV and water intake in the same mice and human subjects. We performed regression analysis in humans, and across the species. Mouse experiment 1: HS+saline study; mouse experiment 2: HS+tap study.